Allogeneic adipose-derived mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by regulating self-reactive T cell responses and dendritic cell function

Abstract

Multipotentmesenchymal stromal cells (MSCs) have emerged as a promising therapy for autoimmune diseases, includingmultiple sclerosis (MS). Administration of MSCs to MS patients has proven safe with signs of immunomodulation but their therapeutic efficacy remains low.The aim of the current study has been to further characterize the immunomodulatorymechanisms of adipose tissue-derivedMSCs (ASCs) in vitro and in vivo using the EAE model of chronic brain inflammation in mice.We found thatmurine ASCs (mASCs) suppress T cell proliferation in vitro via inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 1/2 activities. mASCs also prevented the lipopolysaccharide- (LPS-) induced maturation of dendritic cells (DCs) in vitro.The addition of the COX-1/2 inhibitor indomethacin, but not the iNOS inhibitor L-NAME, reversed the block in DC maturation implicating prostaglandin (PG) E2 in this process. In vivo, early administration of murine and human ASCs (hASCs) ameliorated myelin oligodendrocyte protein- (MOG35-55-) induced EAE in C57Bl/6 mice. Mechanistic studies showed that mASCs suppressed the function of autoantigen-specific T cells and also decreased the frequency of activated (CD11c+CD40high and CD11c+TNF-+) DCs in draining lymph nodes (DLNs). In summary, these data suggest that mASCs reduce EAE severity, in part, through the impairment of DC and T cell function.